Elucidation of the pathogenesis of lethal inherited arrhythmias using iPS cells and development of therapeutic approaches

• Project/Area Number: 19K08538
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyoto University
• Principal Investigator: Makiyama Takeru 京都大学, 医学研究科, 特定講師 (30528302)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 不整脈 / iPS細胞 / 遺伝子 / 心筋細胞 / 疾患モデル / カルモジュリン / リアノジン受容体 / 心筋症 / 遺伝性不整脈

Outline of Research at the Start

QT延長症候群等の遺伝性不整脈疾患は、心臓イオンチャネルの遺伝子変異により心室頻拍・細動を生じ、失神、突然死を来し得る。本研究では、このような家族性不整脈疾患を対象に、発症機序解明、新規治療薬開発を目的とし、臨床・基礎研究を行う。特に、基礎研究では、疾患特異的ヒト人工多能性幹(iPS)細胞研究を進行中であり、最新のゲノム編集技術を用いたiPS細胞株作製、分化心筋細胞のハイスループット解析系の確立を行い、詳細なヒトiPS細胞由来心筋モデルを用いた疾患表現型の再現、発症メカニズムの解明を行い、新規治療法開発を目指す。

Outline of Final Research Achievements

In this study, we aimed to elucidate the pathogenesis of inherited arrhythmias and to develop therapeutic methods, using disease-specific iPS cells (iPSCs). We identified a de novo heterozygous mutation, CALM2 p.E46K in a catecholaminergic polymorphic ventricular tachycardia (CPVT) patient who suffered exercise-induced syncope with ventricular tachycardias. CALM2-E46K iPSC-cardiomyocytes (CMs) exhibited significantly higher frequency of triggered activities and abnormal Ca2+ release events than controls. Larger Ca2+ leak via cardiac ryanodine receptors (RyR2) and smaller Ca2+ storage in sarcoplasmic reticulum observed in E46K-iPSC-CMs. Furthermore, we revealed a dominant facilitative effect of E46K-CaM on RyR2 using biochemical analyses. Thus, we, for the first time, established a CALM-related CPVT iPSC model which successfully recapitulated severe arrhythmogenic features and the iPSC model provides a powerful platform in developing precision medicine.

Academic Significance and Societal Importance of the Research Achievements

遺伝性致死性不整脈疾患は器質的心疾患のない若年者にも突然死を来し得り、社会的影響が大きく、根本的な治療法が確立されていない。本研究対象のカルモジュリン変異による遺伝性不整脈疾患は、稀ではあるが非常に重篤な不整脈を呈する。我々は、カルモジュリン変異によるカテコラミン誘発性多形性心室頻拍のiPS細胞モデルを初めて確立し、重度の催不整脈性を再現することに成功した。また、本モデルを用いた薬効評価の知見は治療法に関するアンメット・メディカル・ニーズが大きい本疾患において臨床的に大きな意義があると考えられ、今後の新規治療法開発の強力なプラットフォームとなり精密医療への貢献が期待される。

Research Products

• [Journal Article] JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias (2022)
  • Author(s): Ono K, Iwasaki YK, Akao M, Makiyama T, Maruyama M, Miake J, Muraji S, Murata H, Morita N, Yokoshiki H, Yoshioka K, Yodogawa K, Inoue H, Okumura K, Kimura T, Tsutsui H, Shimizu W
  • Journal Title: Circulation Journal Volume: 86 Issue: 11 Pages: 1790-1924
  • DOI: 10.1253/circj.CJ-20-1212
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2022-10-25
  • Peer Reviewed / Open Access
• [Journal Article] Oral Adrenergic Agents Produced Ventricular Fibrillation and QT Prolongation in an Elderly Patient Carrying an <i>RYR2</i> Variant (2022)
  • Author(s): Hasegawa Kanae、Gao Jingshan、Ohno Seiko、Ishida Kentaro、Miyazaki Shinsuke、Makiyama Takeru、Horie Minoru、Uzui Hiroyasu、Tada Hiroshi
  • Journal Title: International Heart Journal Volume: 63 Issue: 2 Pages: 398-403
  • DOI: 10.1536/ihj.21-543
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2022-03-30
  • Peer Reviewed
• [Journal Article] Association Between Deleterious SCN5A Variants and Ventricular Septal Defect in Young Patients With Brugada Syndrome (2022)
  • Author(s): Suzuki Keisuke、Sonoda Keiko、Aoki Hisaaki、Nakamura Yuko、Watanabe Seiichi、Yoshida Yoko、Hoshino Kenji、Ozawa Junichi、Imamura Tomohiko、Aiba Takeshi、Kato Koichi、Makiyama Takeru、Kusano Kengo、Horie Minoru、Ohno Seiko
  • Journal Title: JACC: Clinical Electrophysiology Volume: 8 Issue: 3 Pages: 297-305
  • DOI: 10.1016/j.jacep.2022.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1 (2022)
  • Author(s): Shimamoto K, Ohno S, Kato K, Takayama K, Sonoda K, Fukuyama M, Makiyama T, Okamura S, Asakura K, Imanishi N, Kato Y, Sakaguchi H, Kamakura T, Wada M, Yamagata K, Ishibashi K, Inoue Y, Miyamoto K, Nagase S, Kusano K, Horie M, Aiba T.
  • Journal Title: Heart Volume: - Issue: 11 Pages: 2021-320220
  • DOI: 10.1136/heartjnl-2021-320220
  • Peer Reviewed / Open Access
• [Journal Article] School-based routine screenings of electrocardiograms for the diagnosis of long QT syndrome (2022)
  • Author(s): Fukuyama Megumi、Horie Minoru、Aoki Hisaaki、Ozawa Junichi、Kato Koichi、Sawayama Yuichi、Tanaka-Mizuno Sachiko、Makiyama Takeru、Yoshinaga Masao、Nakagawa Yoshihisa、Ohno Seiko
  • Journal Title: EP Europace Volume: - Issue: 9 Pages: 1496-1503
  • DOI: 10.1093/europace/euab320
  • Peer Reviewed
• [Journal Article] Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome (2021)
  • Author(s): Hirose Sayako、Murayama Takashi、Tetsuo Naoyuki、Hoshiai Minako、Kise Hiroaki、Yoshinaga Masao、Aoki Hisaaki、Fukuyama Megumi、Wuriyanghai Yimin、Wada Yuko、Kato Koichi、Makiyama Takeru、Kimura Takeshi、Sakurai Takashi、Horie Minoru、Kurebayashi Nagomi、Ohno Seiko
  • Journal Title: EP Europace Volume: 24 Issue: 3 Pages: 497-510
  • DOI: 10.1093/europace/euab250
  • Peer Reviewed / Open Access
• [Journal Article] <i>Pueraria mirifica</i> , an estrogenic tropical herb, unveiled the severity of Type 1 LQTS caused by <i>KCNQ1</i> ‐T587M (2021)
  • Author(s): Kashiwa Asami、Hosaka Yukio、Takahashi Kazuyoshi、Ohno Seiko、Wada Yuko、Makiyama Takeru、Oda Hirotaka、Horie Minoru
  • Journal Title: Journal of Arrhythmia Volume: 37 Issue: 4 Pages: 1114-1116
  • DOI: 10.1002/joa3.12576
  • Peer Reviewed
• [Journal Article] 【特集/不整脈診療・治療の最新のトピックス】『解説4．iPS心筋細胞の基礎と不整脈、心電学への応用最前線』ヒトiPS細胞モデルを用いた遺伝性不整脈疾患の基礎研究－診断、発症機序解明、新規治療法開発― (2021)
  • Author(s): 牧山 武、山本 雄太、吉永 大介、廣瀬 紗也子、相澤 卓範、柏 麻美、高 景山、今村 知彦、黄 海、糀谷 泰彦
  • Journal Title: 循環器内科 Volume: 90(4) Pages: 483-490
• [Journal Article] Laminopathyモデル (2021)
  • Author(s): 牧山 武、烏日揚海 伊敏、黄 海
  • Journal Title: 疾患モデルの作製と利用―循環器疾患2021 Volume: -
• [Journal Article] Impact of the T-wave characteristics on distinguishing arrhythmogenic right ventricular cardiomyopathy from healthy children (2021)
  • Author(s): Imamura Tomohiko、Sumitomo Naokata、Muraji Shota、Yasuda Kazushi、Nishihara Eiki、Iwamoto Mari、Tateno Shigeru、Doi Shozaburo、Hata Tadayoshi、Kogaki Shigetoyo、Horigome Hitoshi、Ohno Seiko、Ichida Fukiko、Nagashima Masami、Makiyama Takeru、Yoshinaga Masao
  • Journal Title: International Journal of Cardiology Volume: 323 Pages: 168-174
  • DOI: 10.1016/j.ijcard.2020.08.088
  • Peer Reviewed / Open Access
• [Journal Article] Corrigendum to “A challenge for mutation specific risk stratification in long QT syndrome type 1” [J. Cardiol. 72(1) (2018) 56?65] (2021)
  • Author(s): Yagi Noriaki、Itoh Hideki、Hisamatsu Takashi、Tomita Yukinori、Kimura Hiromi、Fujii Yusuke、Makiyama Takeru、Horie Minoru、Ohno Seiko
  • Journal Title: Journal of Cardiology Volume: 77 Issue: 3 Pages: 322-326
  • DOI: 10.1016/j.jjcc.2020.09.008
  • Peer Reviewed
• [Journal Article] Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model (2020)
  • Author(s): Hirose Sayako、Makiyama Takeru、Melgari Dario、Yamamoto Yuta、Wuriyanghai Yimin、Yokoi Fumika、Nishiuchi Suguru、Harita Takeshi、Hayano Mamoru、Kohjitani Hirohiko、Gao Jingshan、Kashiwa Asami、Nishikawa Misato、Wu Jie、Yoshimoto Jun、Chonabayashi Kazuhisa、Ohno Seiko、Yoshida Yoshinori、Horie Minoru、Kimura Takeshi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 761-761
  • DOI: 10.3389/fcell.2020.00761
  • Peer Reviewed / Open Access
• [Journal Article] Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome (2020)
  • Author(s): Lahrouchi N, Tadros R, Crotti L, Makiyama T et al.
  • Journal Title: Circulation Volume: 142 Issue: 4 Pages: 324-338
  • DOI: 10.1161/circulationaha.120.045956
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls (2020)
  • Author(s): 2.Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, et al.
  • Journal Title: Genetics in Medicine Volume: 23 Issue: 1 Pages: 47-58
  • DOI: 10.1038/s41436-020-00946-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SCN5A mutation identified in a patient with short-coupled variant of torsades de pointes (2020)
  • Author(s): Sonoda Keiko、Ohno Seiko、Shimizu Yukiko、Kaitani Kazuaki、Makiyama Takeru、Nakagawa Yoshihisa、Horie Minoru
  • Journal Title: Pacing and Clinical Electrophysiology Volume: - Issue: 5 Pages: 456-461
  • DOI: 10.1111/pace.13924
  • Peer Reviewed
• [Journal Article] An NGS-based genotyping in LQTS; minor genes are no longer minor (2020)
  • Author(s): Ohno Seiko、Ozawa Junichi、Fukuyama Megumi、Makiyama Takeru、Horie Minoru
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 12 Pages: 1083-1091
  • DOI: 10.1038/s10038-020-0805-z
  • Peer Reviewed / Open Access
• [Journal Article] LMNA Missense Mutation Causes Nonsense-Mediated mRNA Decay and Severe Dilated Cardiomyopathy (2020)
  • Author(s): Kato Koichi、Ohno Seiko、Sonoda Keiko、Fukuyama Megumi、Makiyama Takeru、Ozawa Tomoya、Horie Minoru
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 13 Issue: 5 Pages: 435-443
  • DOI: 10.1161/circgen.119.002853
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells (2020)
  • Author(s): Turker I, Makiyama T, Ueyama T, Shimizu A, Yamakawa M, Chen PS, Vatta M, Horie M, Ai T
  • Journal Title: Pacing Clin Electrophysiol Volume: 43 Issue: 8 Pages: 838-846
  • DOI: 10.1111/pace.13996
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Optical Recording of Action Potentials in Human Induced Pluripotent Stem Cell-Derived Cardiac Single Cells and Monolayers Generated from Long QT Syndrome Type 1 Patients (2019)
  • Author(s): Takaki Tadashi、Inagaki Azusa、Chonabayashi Kazuhisa、Inoue Keiji、Miki Kenji、Ohno Seiko、Makiyama Takeru、Horie Minoru、Yoshida Yoshinori
  • Journal Title: Stem Cells International Volume: 2019 Pages: 1-12
  • DOI: 10.1155/2019/7532657
  • NAID: 120006634620
  • Peer Reviewed / Open Access
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells (2019)
  • Author(s): Yoshinaga Daisuke、Baba Shiro、Makiyama Takeru、Shibata Hirofumi、Hirata Takuya、Akagi Kentaro、Matsuda Koichi、Kohjitani Hirohiko、Wuriyanghai Yimin、Umeda Katsutsugu、Yamamoto Yuta、Conklin Bruce R.、Horie Minoru、Takita Junko、Heike Toshio
  • Journal Title: Stem Cell Reports Volume: 13 Issue: 2 Pages: 394-404
  • DOI: 10.1016/j.stemcr.2019.06.007
  • NAID: 120006786948
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A de novo gain-of-function KCND3 mutation in early repolarization syndrome (2019)
  • Author(s): Takayama Koichiro、Ohno Seiko、Ding Wei-Guang、Ashihara Takashi、Fukumoto Daisuke、Wada Yuko、Makiyama Takeru、Kise Hiroaki、Hoshiai Minako、Matsuura Hiroshi、Horie Minoru
  • Journal Title: Heart Rhythm Volume: 16 Issue: 11 Pages: 1698-1706
  • DOI: 10.1016/j.hrthm.2019.05.033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ブルガダ症候群におけるアルコール代謝酵素の遺伝子変異 飲酒後の失神に関する知見(Genetic Variants of Alcohol-Metabolizing Enzymes in Brugada Syndrome: Insights into Syncope after Drinking Alcohol) (2019)
  • Author(s): Qi Wu,Hideki Hayashi,Daiki Hira,Keiko Sonoda,Satoshi Ueshima,Seiko Ohno,Takeru Makiyama,Tomohiro Terada,Toshiya Katsura,Katsuyuki Miura,Minoru Horie
  • Journal Title: Journal of Arrhythmia Volume: 35 Pages: 752-759
  • Peer Reviewed
• [Journal Article] Expertise ヒトiPS細胞由来心筋細胞の電気生理学 (特集 心臓電気生理を理解して不整脈診療に活かす) iPS cell-derived cardiomyocytes as a platform for research on inherited arrhythmias (2019)
  • Author(s): 堀江 稔,Wuriyanghai Yimin,牧山 武
  • Journal Title: Heart view Volume: 23 Pages: 578-585
• [Journal Article] Calmodulinopathy(カルモジュリン遺伝子関連不整脈疾患) iPS細胞技術を用いた疾患モデルの作製と遺伝子治療へのアプローチ (2019)
  • Author(s): 山本 雄大,牧山 武
  • Journal Title: 心電図 Volume: 39 Pages: 273-282
  • NAID: 130007903608
• [Presentation] Modeling Inherited Arrhythmias using Patient-derived iPS Cells. -Calmodulinopathy- (2022)
  • Author(s): Takeru Makiyama
  • Organizer: 第86回日本循環器学会学術集会（JCS2022）
  • Invited
• [Presentation] Modeling RYR2-related Long-QT Syndrome using iPS Cell Model Generated by CRISPR/Cas9-based Knock-in Genome Editing Technology (2022)
  • Author(s): Jingshan Gao, Takeru Makiyama, Seiko Ohno, Yuta Yamamoto, Asami Kashiwa, Tomohiko Imamura, Takanori Aizawa, Hai Huang, Hirohiko Kohjitani, Minoru Horie, Takeshi Kimura
  • Organizer: 第86回日本循環器学会学術集会（JCS2022）
• [Presentation] Clinical aspects of Brugada syndrome in children: the impact of gender and age on the prognosis (2022)
  • Author(s): Tomohiko Imamura, Takeru Makiyama, Junichi Ozawa,Hai Huang, Takanori Aizawa, Jingshan Gao, Asami Kashiwa, Hirohiko Kohjitani, Koichi Kato, Hiroshi Suzuki, Keiko Sonoda, Seiko Ohno, Naokata Sumitomo, Minoru Horie, Takeshi Kimura
  • Organizer: 第86回日本循環器学会学術集会（JCS2022）
• [Presentation] 乳幼児突然死症例における遺伝性不整脈の関与と死亡状況の検討 (2022)
  • Author(s): 今村知彦，牧山武，大野聖子, 堀江稔
  • Organizer: 第27回日本SIDS・乳幼児突然死予防学会
• [Presentation] iPS細胞由来心筋細胞の電気生理学的特徴と遺伝性不整脈疾患モデルの検討 (2021)
  • Author(s): 牧山 武
  • Organizer: 心電学関連春季大会2021
  • Invited
• [Presentation] Inhibition of Late Sodium Current Shortens Action Potential Durations in CACNA1C-E1115K iPS Cell Model with Disrupted Cav1.2 Ion Selectivity (2021)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Thomas Maurissen, Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Hai Huang, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: 第67回日本不整脈心電学会学術集会（JHRS2021）
• [Presentation] 小児Brugada症候群の臨床的・遺伝学的特徴：年齢、性ホルモンの影響 (2021)
  • Author(s): 今村知彦、牧山武、小澤淳一、加藤浩一、大野聖子、鈴木博、住友直方、堀江稔
  • Organizer: 第25回小児心電学会
  • Invited
• [Presentation] Modeling Novel Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)-Associated Calmodulin Mutation CALM2-E46K using iPS cells (2021)
  • Author(s): Jingshan Gao, Takeru Makiyama, Yuta Yamamoto, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Hirohiko Kohjitani, Kouichi Kato, Seiko Ohno, Minoru Horie, Takeshi Kimura
  • Organizer: 第5回日本循環器学会基礎研究フォーラム（BCVR2021）
  • Invited
• [Presentation] Modeling Inherited Arrhythmias Associated with Ryanodine Receptor Dysfunction using iPS Cells (2021)
  • Author(s): Takeru Makiyama, Jingshan Gao, Yuta Yamamoto, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Hirohiko Kohjitani, Kouichi Kato, Taisuke Ishikawa, Hisaaki, Aoki, Futoshi Toyoda, Knut Wolten, Yoshinori Yoshida, Seiko Ohno, Naomasa Makita, Minoru Horie, Takeshi Kimura
  • Organizer: 第85回日本循環器学会学術集会（JCS2021）
• [Presentation] Development of an Oligonucleotide-Based Therapeutic Approach for Calmodulinopathy (2021)
  • Author(s): Takeru Makiyama, Yuta Yamamoto, Yoshiki Kondo, Jingshan Gao, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Hirohiko Kohjitani, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Naomasa Makita, Minoru Horie, Takeshi Kimura
  • Organizer: 第85回日本循環器学会学術集会（JCS2021）
• [Presentation] iPS Cell-Based Inherited Arrhythmia Disease Modeling. iPSCs: Limitations and Future challenges. Cardiac Arrhythmias (2020)
  • Author(s): Takeru Makiyama
  • Organizer: 第84回日本循環器学会学術集会（JCS2020）
  • Invited
• [Presentation] 患者由来iPS細胞分化心筋モデルを用いた不整脈疾患の病態解析、創薬への応用 (2020)
  • Author(s): 牧山武
  • Organizer: 第97回日本生理学会大会
  • Invited
• [Presentation] Preclinical Proof-of-Concept Study: Antisense-mediated Knockdown of CALM as a Therapeutic Strategy for Calmodulinopathy (2020)
  • Author(s): Yuta Yamamoto, Takeru Makiyama, Yoshiki Kondo, Yusuke Iriyama, Ryutarou Ishikawa, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: European Society of Cardiology (ESC) Congress 2020
  • Int'l Joint Research
• [Presentation] Inhibition of Late Sodium Current Attenuates Prolonged Action Potential Durations in CACNA1C-E1115K iPS Cell Model with Disrupted Cav1.2 ion Selectivity (2020)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Thomas Maurissen, Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Hai Huang, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: The Heart Rhythm Society's Annual Scientific Sessions 2020 (HRS2020)
  • Int'l Joint Research
• [Presentation] Clinical and genetic aspects of pediatric Brugada syndrome (2020)
  • Author(s): Tomohiko Imamura, Takeru Makiyama, Hai Huang, Takanori Aizawa, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Yasuhiko Kohjitani, Koichi Kato, Seiko Ohno, Naokata Sumitomo, Minoru Horie.
  • Organizer: European Society of Cardiology (ESC) Congress 2020
  • Int'l Joint Research
• [Presentation] Human Induced Pluripotent Stem Cell Model of CACNA1C-E1115K which Impairs Ion Selectivity of the Cardiac L-type Calcium Channel (2020)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Thomas Maurissen, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Jungshan Gao, Huang Hai, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura.
  • Organizer: 第84回日本循環器学会学術集会（JCS2020）
• [Presentation] CALM2-N98S Mutation Associated with Long QT Syndrome Impaired the Response of KCNQ1 Channel to Beta-adrenergic Stimulation in Human iPSC-derived Cardiomyocytes. (2020)
  • Author(s): Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Hideki Motomura, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura.
  • Organizer: 第84回日本循環器学会学術集会（JCS2020）
• [Presentation] Preclinical Proof-of-concept of Antisense-mediated Transcript Knockdown Therapy in Calmodulinopathy (2020)
  • Author(s): Yuta Yamamoto, Takeru Makiyama, Yoshiki Kondo, Yusuke Iriyama, Ryutarou Ishikawa, Jingshan Gao, Hirohiko Kohjitani, Asami Kashiwa, Takanori Aizawa, Tomohiko Imamura, Hai Huang, Taisuke Ishikawa, Yoshinori Yoshida, Seiko Ohno, Minoru Horie, Naomasa Makita, Takeshi Kimura.
  • Organizer: 第14回日本循環器学会基礎研究フォーラム（BCVR2020）
• [Presentation] Inhibition of Late Sodium Current Attenuates Prolonged Action Potential Durations in CACNA1C-E1115K iPS Cell Model with Disrupted Cav1.2 ion Selectivity (2020)
  • Author(s): Asami Kashiwa, Takeru Makiyama et al.
  • Organizer: 第14回日本循環器学会基礎研究フォーラム（BCVR2020）
• [Presentation] 患者由来iPS細胞モデルを用いたCav 1.2イオン選択性を障害するCACNA1C-E1115K変異がQT延長症候群、Brugada症候群を発症するメカニズムの解析 (2020)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Thomas Maurissen, Yimin Wuriyanghai, Yuta Yamamoto, Jiungshan Gao, Huang Hai, Tomohiko Imamura, Takanori Aizawa, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiich Sato, Kazuhiro Takahashi, Knut Woltjen, Minoru Horie, Naomasa Makita, Takeshi Kimura.
  • Organizer: 第97回日本生理学会大会
• [Presentation] Modeling Overlap Syndrome Of Long QT And Brugada Syndrome Associated With CACNA1C-E1115K Which Alters Ion Selectivity With Induced Pluripotent Stem Cells (2019)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Gao Jungshan, Hai Huang, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, , Seiichi Sato, Minoru Horie , Naomasa Makita, Takeshi Kimura.
  • Organizer: 40th Heart Rhythm Scientific Sessions
  • Int'l Joint Research
• [Presentation] Automatic Computational Action Potential Analyzing System Enables Accurate Drug Response Interpretation and Prediction in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes (2019)
  • Author(s): Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Minoru Horie, Takeshi Kimura, Akinori Noma, Akira Amano.
  • Organizer: 40th Heart Rhythm Scientific Sessions
  • Int'l Joint Research
• [Presentation] Structural Insights into Catecholaminergic Polymorphic Ventricular Tachycardia-associated RyR2 Mutant Channels using a Three-dimensional In Silico Model. (2019)
  • Author(s): J. Gao, T. Makiyama, S. Ohno, Y. Yamamoto, Y. Wuriyanghai, H. Kohjitani, A. Kashiwa, H. Huang, K. Katou, M. Horie, T. Kimura.
  • Organizer: European Society of Cardiology Congress 2019
  • Int'l Joint Research
• [Presentation] KCNQ1 Channel Dysfunction in human induced pluripotent stem cell-derived cardiomyocytes carrying a CALM2-N98S mutation associated with long QT syndrome (2019)
  • Author(s): Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Morphological and electrophysiological characterization of homozygous lamin A/C knockout human induced-pluripotent stem cell-derived cardiomyocytes. American Heart Association Scientific Sessions 2019 (2019)
  • Author(s): Yimin Wuriyanghai, Takeru Makiyama, Yuta Yamamoto, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Hai Huang, Takanori Aizawa, Tomohiko Imamura, Seiko Ohno, Minoru Horie, Takeshi Kimura
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Response of KCNQ1 to Adrenergic Stimulation was Impaired in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes Carrying a CALM2-N98S Mutation Associated with Long QT Syndrome. (2019)
  • Author(s): Yuta Yamamoto, Takeru Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: 12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
  • Int'l Joint Research
• [Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing. (2019)
  • Author(s): Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Asami Kashiwa, Yimin Wuriyanghai, Yuta Yamamoto, Minoru Horie, Takeshi Kimura, Akinori Noma, Akira Amano
  • Organizer: 12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
  • Int'l Joint Research
• [Presentation] Patients characteristics of idiopathic ventricular fibrillation carrying SCN5A mutations without Brugada or long QT syndrome. (2019)
  • Author(s): Takanori Aizawa, Takeru Makiyama, Hai Huang, Tomohiko Imamura, JingShan Gao, Yimin Wuriyanghai, Takeru Makiyama, Yuta Yamamoto, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Hai Huang, Wuriyanghai Yimin, Hirohiko Kohjitani, Yuta Yamamoto, Seiko Ohno, Minoru Horie
  • Organizer: 12th Asia Pacific Heart Rhythm Society Scientific Session (APHRS2019)
  • Int'l Joint Research
• [Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing (2019)
  • Author(s): Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Hai Huang, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Daisuke Yoshinaga, Takeshi Kimura, Akira Amano.
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Overlapping Sick Sinus Syndrome Associated with SCN5A Mutations in Patients with Brugada Syndrome (2019)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Seiko Ohno, Hisaaki Aoki, Hirohiko Kohjitani Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Huang Hai, Minoru Horie, Takeshi Kimura.
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Three-Dimensional Structural Analysis of Mutant Ryanodine Receptor Type 2 Channels Associated with Catecholaminergic Polymorphic Ventricular Tachycardia. (2019)
  • Author(s): Jingshan Gao, Takeru Makiyama, Seiko Ohno, Yuta Yamamoto, Yimin Wuriyanghai, Hirohiko Kohjitani, Asami Kashiwa, Minoru Horie, Takeshi Kimura.
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Modeling Overlapping Phenotypes of Long-QT and Brugada Syndrome with CACNA1C-E1115K that Alters Ion Selectivity of the Cardiac L-Type Calcium Channel Using Induced Pluripotent Stem Cells. (2019)
  • Author(s): Asami Kashiwa, Takeru Makiyama, Hirohiko Kohjitani, Yimin Wuriyanghai, Yuta Yamamoto, Jingshan Gao, Hai Huang, Taisuke Ishikawa, Seiko Ohno, Futoshi Toyoda, Seiichi Sato, Minoru Horie, Naomasa Makita, Takeshi Kimura
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing. (2019)
  • Author(s): Hirohiko Kohjitani, Shigeya Kouda, Yukiko Himeno, Takeru Makiyama, Hai Huang, Jingshan Gao, Asami Kashiwa, Yimin Wuriyanghai, Daisuke Yoshinaga, Takeshi Kimura, Akira Amano.
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Single Cell Electrophysiological Analysis of iPS Cell-derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Potential Imaging System. (2019)
  • Author(s): Yuta Yamamoto, Takeru Makiyama(代発表), Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Kenji Suda, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura,
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Structural Insights into Catecholaminergic Polymorphic Ventricular Tachycardia-associated RyR2 Mutant Channels using a Three-dimensional in Silico Model. (2019)
  • Author(s): Jingshan Gao, Takeru Makiyama, Seiko Ohno, Yuta Yamamoto, Yimin Wuriyanghai, Hirohiko Kohjitani, Asami Kashiwa, Hai Huang, Kouichi Katou, Minoru Horie, Takeshi Kimura.
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Phenotype-based High-throughput Classification of Long-QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells. (2019)
  • Author(s): Daisuke Yoshinaga, Shiro Baba, Takeru Makiyama, Hirofumi Shibata, Takuya Hirata, Kentaro Akagi, Koichi Matsuda, Hirohiko Kohjitani, Yimin Wuriyanghai, Katsutsugu Umeda, Yuta Yamamoto, Bruce R. Conklin, Minoru Horie, Junko Takita, Toshio Heike.
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Complex aberrant splicing in the induce pluripotent stem cell-derived cardiomyocytes from a patient with long-QT syndrome carrying KCNQ1-A344Aspl mutation. (2019)
  • Author(s): Wuriyanghai Y, Makiyama T, Sasaki K, Kamakura T, Yamamoto Y, Hayano M, Harita T, Nishiuchi S, Chen J, Kohjitani H, Hirose S, Yokoi F, Gao J, Chonabayashi K, Watanabe K, Ohno S, Yoshida Y, Kimura T, Horie M
  • Organizer: 第66回日本不整脈心電学会学術大会
• [Presentation] Challenges of iPS cell-Based Disease Modeling and Therapeutic Approaches to Inherited Arrhythmias (2019)
  • Author(s): Takeru Makiyama
  • Organizer: 第 3回日本循環器学会基礎研究フォーラム
  • Invited
• [Patent(Industrial Property Rights)] アンチセンスオリゴヌクレオチド医薬のスクリーニング方法 (2020)
  • Inventor(s): 牧山武、山本雄大、入山友輔、近藤嘉紀、日高夕貴、石川龍太郎
  • Industrial Property Rights Holder: 牧山武、山本雄大、入山友輔、近藤嘉紀、日高夕貴、石川龍太郎
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-036716
  • Filing Date: 2020
• [Patent(Industrial Property Rights)] ＣＡＬＭ２のアンチセンスオリゴヌクレオチド (2020)
  • Inventor(s): 入山友輔、近藤嘉紀、日高夕貴、石川龍太郎、牧山武、山本雄大
  • Industrial Property Rights Holder: 入山友輔、近藤嘉紀、日高夕貴、石川龍太郎、牧山武、山本雄大
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-036715
  • Filing Date: 2020